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Disulfiram, an old drug with new potential therapeutic uses for human hematological malignancies
Author(s) -
Conticello Concetta,
Martinetti Daniela,
Adamo Luana,
Buccheri Simona,
Giuffrida Raffaella,
Parrinello Nunziatina,
Lombardo Laura,
Anastasi Gabriele,
Amato Gabriella,
Cavalli Maide,
Chiarenza Annalisa,
De Maria Ruggero,
Giustolisi Rosario,
Gulisano Massimo,
Di Raimondo Francesco
Publication year - 2012
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.27482
Subject(s) - disulfiram , cancer research , aldehyde dehydrogenase , apoptosis , pharmacology , reactive oxygen species , chemotherapy , caspase , in vivo , haematopoiesis , multiple myeloma , medicine , acetylcysteine , drug , myeloid leukemia , immunology , biology , programmed cell death , antioxidant , stem cell , biochemistry , microbiology and biotechnology , enzyme
Disulfiram (DSF) is an aldehyde dehydrogenase inhibitor currently used for the treatment of alcoholism. Here, we show that multiple myeloma (MM) cell lines and primary cells from newly diagnosed and relapsed/resistant patients affected by MM, acute myeloid and lymphoblastic leukemia are significantly sensitive to DSF alone and in combination with copper. These effects are present at doses lower than those achievable in vivo after DSF standard administration. The cytotoxic effect achieved by this treatment is comparable to that obtained by conventional chemotherapy and is absent in normal hematopoietic cells. In addition, we found that DSF plus copper induces loss of mitochondrial membrane potential, triggers reactive oxygen species (ROS) production and activates executioner caspases. DSF‐copper‐induced apoptosis and caspases activation are strongly reversed by antioxidant N ‐acetylcysteine, thus indicating a critical role of ROS. These results might suggest the use of the old drug DSF, alone or in combination with copper, in the treatment of hematological malignancies.